Recently I ran into an issue where WordPress would take a long time to update rewrite rules after saving a page or post and my PHP error log would contain entries similar to:

WordPress database error MySQL server has gone away for query INSERT INTO wp_options (option_name, option_value, autoload) VALUES ('rewrite_rules', '<serialized array>, 'yes')

In addition to various defaults the serialized array contains 9 regular expressions for every page and post.

(PAGENAME)/trackback/?$
(PAGENAME)/feed/(feed|rdf|rss|rss2|atom)/?$
(PAGENAME)/(feed|rdf|rss|rss2|atom)/?$
(PAGENAME)/page/?([0-9]{1,})/?$
(PAGENAME)(/[0-9]+)?/?$
PAGENAME/attachment/([^/]+)/?$
PAGENAME/attachment/([^/]+)/trackback/?$
PAGENAME/attachment/([^/]+)/feed/(feed|rdf|rss|rss2|atom)/?$
PAGENAME/attachment/([^/]+)/(feed|rdf|rss|rss2|atom)/?$

Each post you add increases the size of the rewrite_rules array and puts you one step closer to the breaking point - MySQL's max_allowed_packet variable. By default this is 1MB which means that the size of your statements must be less than that, and the largest row you can retrieve is 1MB. I hit the 1MB limit at around 820 pages.

It's an easy fix; add max_allowed_packet=16M (or however large you'd like to make it) to your MySQL configuration in the [mysqld] section.